Dosage and formulation

ABSTRACT

The present disclosure relates to pharmaceutical compositions for inhalation comprising aclidinium in the form of a dry powder of a pharmaceutically acceptable salt in admixture with a pharmaceutically acceptable dry powder carrier, providing a metered nominal dose of aclidinium equivalent to about 400 micrograms aclidinium bromide.

This is a continuation of application Ser. No. 12/921,921, which wasfiled on Sep. 10, 2010, and has a § 371 date of Oct. 5, 2010, and whichis the U.S. national stage application of International PatentApplication No. PCT/EP2009/001832 filed on Mar. 13, 2009, which claimspriority of European Patent Application No. 08382010.0, filed on Mar.13, 2008. The content of all of these applications are incorporatedherein by reference.

This invention relates to a novel dosage for aclidinium and to novelmethods and formulations for the treatment of respiratory diseases,especially asthma and chronic obstructive pulmonary disease (COPD),using aclidinium.

BACKGROUND

Aclidinium bromide is3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octanebromide, described in, e.g., WO 0104118. Although this compound is knownto be along-acting anticholinergic useful in the treatment ofrespiratory diseases, the optimal dosage is not disclosed.

SUMMARY OF THE INVENTION

It is now surprisingly found that, for treatment of respiratorydisorders, particularly asthma and COPD, in an adult human, aclidiniumis most effective upon administration by inhalation in a dosage of about400 μg metered nominal dose, typically a single dosage of about 400micrograms per day metered nominal dose, (e.g., about 360 μg emitteddose, and about 120 μg Fine Particle dose) (weight corresponding toaclidinium bromide).

The invention thus provides in a first embodiment a pharmaceuticalcomposition for inhalation comprising aclidinium in the form of a drypowder of a pharmaceutically acceptable salt, e.g., aclidinium bromide,in admixture with a pharmaceutically acceptable dry powder carrier,e.g., lactose particles, (i) comprising a single metered nominal dose ofaclidinium equivalent to about 400 μg aclidinium bromide, or (ii) in amultidose dry powder inhaler device calibrated to provide a meterednominal dose of aclidinium equivalent to about 400 μg aclidiniumbromide. This composition can be administered one or more times per day.Preferably once or twice a day.

In a second embodiment, the invention provides a method of treating arespiratory condition, e.g., selected from asthma and chronicobstructive pulmonary disease, in a patient in need of such treatment,comprising administering a dose, typically a single daily dose or twicedaily dose, of aclidinium, e.g., aclidinium bromide, equivalent to about400 μg metered nominal dose aclidinium bromide, e.g., comprisingadministering a pharmaceutical composition according to the previousparagraph. The invention further provides the use of aclidinium in themanufacture of a medicament, e.g., as described in the precedingparagraph, for use in such a method.

The aclidinium may be administered as monotherapy, or in combinationwith one or more additional anti-inflammatory and/or bronchodilatingagents, e.g., corticosteroids, PDE IV inhibitors and β2-agonists, e.g.,formoterol, salmeterol, budesonide, and mometasone, and the inventionthus further provides methods as described above further comprisingadministration of an effective amount of such an agent, as well aspharmaceutical compositions as described above, further comprising suchadditional agent(s).

DETAILED DESCRIPTION OF THE INVENTION

Typically, the aclidinium is administered in the form of a salt with ananion X, wherein X is a pharmaceutically acceptable anion of a mono orpolyvalent acid. More typically, X is an anion derived from an inorganicacid, such as hydrochloric acid, hydrobromic acid, sulphuric acid andphosphoric acid, or an organic acid such as methanesulphonic acid,acetic acid, fumaric acid, succinic acid, lactic acid, citric acid ormaleic acid. Preferably the aclidinium is in the form of aclidiniumbromide.

The aclidinium is preferably administered in the form of a dry powder,in admixture with a suitable carrier, e.g., lactose powder, suitable forinhalation.

For example, in one embodiment, the aclidinium is aclidinium bromide inadmixture with lactose powder.

The respiratory disease or condition to be treated with the formulationsand methods of the present invention is typically asthma, acute orchronic bronchitis, emphysema, chronic obstructive pulmonary disease(COPD), bronchial hyperreactivity or rhinitis, in particular asthma orchronic obstructive pulmonary disease (COPD), especially COPD.

In the context of dosage of an active agent, “about” as used hereinmeans within the normal limits of acceptable variations as defined bythe European and US Pharmacopeia of plus/minus 35% or preferablyacceptable variations as defined by the current most stringentrequirement, the US FDA draft guidance for inhaler of plus/minus 25% orespecially within the metered dosing accuracy for the dispensing systeme.g. +/−10% Thus a metered nominal dose of “about 400 μg” is meant atarget dose of 400 μg subject to variation within the normal limits ofacceptance for the dispensing system, e.g. plus/minus 35% (acceptablevariations as defined by the European and US Pharmacopeia) or preferably300-500 μg (or acceptable variations as defined by the current moststringent requirement, the US FDA draft guidance for inhaler) orespecially 340-460 μg (or within the metered dosing accuracy of theinhaler).

The emitted dose and the fine particle dose (fine particle dose=μgaclidinium bromide in the emitted dose below a cut off aerodynamicthreshold of 5 micrometer) are subjected to the same variation andproportional to the metered dose and are therefore for the emitted dosee.g. a metered nominal dose of about 400 μg (plus/minus 35%) correspondsto about 360 μg emitted dose (plus/minus 35%), and about 120 microgramsFine Particle dose (plus/minus 35%)

Packaging of the formulation may be suitable for unit dose or multi-dosedelivery. In the case of multi-dose delivery, the formulation can bepre-metered or metered in use. Dry powder inhalers are thus classifiedinto three groups: (a) single dose, (b) multiple unit dose and (c) multidose devices.

Formulations generally contain a powder mix for inhalation of thecompounds of the invention and a suitable powder base (carriersubstance) such as lactose or starch. Use of lactose is preferred. Eachcapsule or cartridge may generally contain between 2 μg and 400 μg ofeach therapeutically active ingredient. Alternatively, the activeingredient(s) may be presented without excipients.

For single dose inhalers of the first type, single doses have beenweighed by the manufacturer into small containers, which are mostly hardgelatine capsules. A capsule has to be taken from a separate box orcontainer and inserted into a receptacle area of the inhaler. Next, thecapsule has to be opened or perforated with pins or cutting blades inorder to allow part of the inspiratory air stream to pass through thecapsule for powder entrainment or to discharge the powder from thecapsule through these perforations by means of centrifugal force duringinhalation. After inhalation, the emptied capsule has to be removed fromthe inhaler again. Mostly, disassembling of the inhaler is necessary forinserting and removing the capsule, which is an operation that can bedifficult and burdensome for some patients. Other drawbacks related tothe use of hard gelatine capsules for inhalation powders are (a) poorprotection against moisture uptake from the ambient air, (b) problemswith opening or perforation after the capsules have been exposedpreviously to extreme relative humidity, which causes fragmentation orindenture, and (c) possible inhalation of capsule fragments. Moreover,for a number of capsule inhalers, incomplete expulsion has beenreported.

Some capsule inhalers have a magazine from which individual capsules canbe transferred to a receiving chamber, in which perforation and emptyingtakes place, as described in WO 92/03175. Other capsule inhalers haverevolving magazines with capsule chambers that can be brought in linewith the air conduit for dose discharge (e.g. WO91/02558 and GB2242134). They comprise the type of multiple unit dose inhalers togetherwith blister inhalers, which have a limited number of unit doses insupply on a disk or on a strip.

Blister inhalers provide better moisture protection of the medicamentthan capsule inhalers. Access to the powder is obtained by perforatingthe cover as well as the blister foil, or by peeling off the cover foil.When a blister strip is used instead of a disk, the number of doses canbe increased, but it is inconvenient for the patient to replace an emptystrip. Therefore, such devices are often disposable with theincorporated dose system, including the technique used to transport thestrip and open the blister pockets.

Multi-dose inhalers do not contain pre-measured quantities of the powderformulation. They consist of a relatively large container and a dosemeasuring principle that has to be operated by the patient. Thecontainer bears multiple doses that are isolated individually from thebulk of powder by volumetric displacement. Various dose measuringprinciples exist, including rotatable membranes (e. g. EP0069715) ordisks (e.g. GB 2041763; EP 0424790; DE 4239402 and EP 0674533),rotatable cylinders (e.g. EP 0166294; GB 2165159 and WO 92/09322) androtatable frustums (e.g. WO 92/00771), all having cavities which have tobe filled with powder from the container. Other multi dose devices havemeasuring slides (e.g. U.S. Pat. No. 5,201,308 and WO 97/00703) ormeasuring plungers with a local or circumferential recess to displace acertain volume of powder from the container to a delivery chamber or anair conduit e.g. EP 0505321, WO 92/04068 and WO 92/04928.

Reproducible dose measuring is one of the major concerns for multi doseinhaler devices. The powder formulation has to exhibit good and stableflow properties, because filling of the dose measuring cups or cavitiesis mostly under the influence of the force of gravity. For reloadedsingle dose and multiple unit dose inhalers, the dose measuring accuracyand reproducibility can be guaranteed by the manufacturer. Multi doseinhalers on the other hand, can contain a much higher number of doses,whereas the number of handlings to prime a dose is generally lower.

Because the inspiratory air stream in multi-dose devices is oftenstraight across the dose measuring cavity, and because the massive andrigid dose measuring systems of multi dose inhalers can not be agitatedby this inspiratory air stream, the powder mass is simply entrained fromthe cavity and little de-agglomeration is obtained during discharge.

Consequently, separate disintegration means are necessary. However inpractice, they are not always part of the inhaler design. Because of thehigh number of doses in multi-dose devices, powder adhesion onto theinner walls of the air conduits and the de-agglomeration means must beminimized and/or regular cleaning of these parts must be possible,without affecting the residual doses in the device. Some multi doseinhalers have disposable drug containers that can be replaced after theprescribed number of doses has been taken (e.g. WO 97/000703). For suchsemi-permanent multi dose inhalers with disposable drug containers, therequirements to prevent drug accumulation are even stricter.

In a preferred embodiment, the aclidinium is administered via abreath-activated, multidose, dry powder inhaler, calibrated to permitdaily dosing of 400 μg metered nominal dose of aclidinium. An especiallypreferred inhaler device for this purpose is Genuair®, (formerly knownas Novolizer SD2FL), or as described in WO 97/000703, WO 03/000325, orWO 03/061742, the contents of which applications are incorporated hereinby reference.

Apart from applications through dry powder inhalers the compositions ofthe invention can be administered in aerosols which operate viapropellant gases or by means of so-called atomisers or nebulizers, viawhich solutions or suspensions of pharmacologically-active substancescan be sprayed under high pressure so that a mist of inhalable particlesresults.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum particle size for inhalation into thebronchial system is usually 1-10 μm, preferably 2-5 μm. Particles havinga size above 20μ, are generally too large when inhaled to reach thesmall airways. To achieve these particle sizes the particles of theactive ingredient as produced may be size reduced by conventional meanseg by micronisation or supercritical fluid techniques. The desiredfraction may be separated out by air classification or sieving.Preferably, the particles will be crystalline.

Achieving a high dose reproducibility with micronised powders isdifficult because of their poor flowability and extreme agglomerationtendency. To improve the efficiency of dry powder compositions, theparticles should be large while in the inhaler, but small whendischarged into the respiratory tract. Thus, an excipient, for example amono-, di- or polysaccharide or sugar alcohol, e.g., such as lactose,mannitol or glucose is generally employed. The particle size of theexcipient will usually be much greater than the inhaled medicamentwithin the present invention. When the excipient is lactose it willtypically be present as lactose particles, preferably crystalline alphalactose monohydrate, e.g., having an average particle size range of20-1000 μm, preferably in the range of 90-150 μm. The median particlesize approximately corresponds to the average and is the diameter where50 mass-% of the particles have a larger equivalent diameter, and theother 50 mass-% have a smaller equivalent diameter. Hence the averageparticle size is generally referred to in the art as equivalent d50. Thedistribution of particle size around may affect flow properties, bulkdensity, etc. Hence to characterize a particle size diameter, otherequivalent diameters can be used in addition to d50, such as d10 andd90. d10 is the equivalent diameter where 10 mass-% of the particleshave a smaller diameter (and hence the remaining 90% is coarser). d90 isthe equivalent diameter where 90 mass-% of the particles have a smallerdiameter. In one embodiment, the lactose particles for use informulations of the invention have a d10 of 90-160 μm, a d50 of 170-270μm, and d90 of 290-400 μm.

Suitable lactose materials for use in the present invention arecommercially available, e.g., from DMW Internacional (Respitose GR-001,Respitose SV-001, Respitose SV-003); Meggle (Capsulac 60, Inhalac 70,Capsulac 60 INH); and Borculo Domo (Lactohale 100-200, Lactohale200-300, and Lactohale 100-300).

The ratio between the lactose particles and the aclidinium by weightwill depend on the inhaler device used, but is typically, e.g., 5:1 to100:1, for example 25:1 to 75:1, e.g., 30-35:1.

In a preferred embodiment, the aclidinium is administered in the form ofa dry powder formulation of aclidinium bromide in admixture withlactose, in a ratio by weight of aclidinium to lactose of 1:50 to 1:75,suitable for administration via a dry powder inhaler, wherein theaclidinium particles have an average particle size of from 2 to 5 μm indiameter, e.g., less than 3 μm in diameter, and the lactose particleshave have a d10 of 90-160 μm, a d50 of 170-270 μm, and d90 of 290-400μm.

Additional active agents such as β2-agonists, PDE IV inhibitors,corticosteroids, leukotriene D4 antagonists, inhibitors of egfr-kinase,p38 kinase inhibitors or NK1 receptor agonists may be utilized in themethods and formulations of the inventions. For example, the inventionprovides aclidinium formulations as described herein further comprisingan effective amount of one or more such additional active agents, e.g.further comprising an effective amount of a β2-agonist and/or a PDE IVinhibitor and/or a corticosteroid. The invention also provides methodsfor treating respiratory conditions as herein before described, e.g.,asthma or COPD, comprising administering an aclidinium formulation asdescribed herein and further comprising administering simultaneously aneffective amount of one or more such additional active agents, e.g.further comprising an effective amount of a β2-agonist and/or a PDE IVinhibitor and/or a corticosteroid.

β2-agonists suitable for use with the aclidinium in the presentinvention include, e.g., arformoterol, bambuterol, bitolterol,broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol,hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol,mabuterol, meluadrine, metaprotenerol, nolomirole, orciprenaline,pirbuterol, procaterol, reproterol, ritodrine, rimoterol, salbutamol,salmefamol, salmeterol, sibenadet, sotenerot, sulfonterol, terbutaline,tiaramide, tulobuterol, GSK-597901, milveterol, GSK-678007, GSK-642444,GSK-159802, HOKU-81, LAS100977(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one),KUL-1248, carmoterol, indacaterol and5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanoland1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanoloptionally in the form of their racemates, their enantiomers, theirdiastereomers, and mixtures thereof, and optionally theirpharmacologically-compatible acid addition salts.

The preferred β2-agonists to be used in the combinations of theinvention are: arformoterol, bambuterol, bitolterol, broxaterol,carbuterol, clenbuterol, dopexamine, fenoterol, formoterol,hexoprenaline, ibuterol, isoprenaline, levosalbutamol, mabuterol,meluadrine, nolomirole, orciprenaline, pirbuterol, procaterol,(R,R)-formoterol, reproterol, ritodrine, rimoterol, salbutamol,salmeterol, sibenadet, sulfonterol, terbutaline, tulobuterol,GSK-597901, milveterol, LAS100977(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one),KUL-1248, carmoterol and indacaterol optionally in the form of theirracemates, their enantiomers, their diastereomers, and mixtures thereof,and optionally their pharmacologically-compatible acid addition salts.

Since the M3 antagonists of the invention have a long duration ofaction, it is preferred that they are combined with long-actingβ2-agonists (also known as LABAs). The combined drugs could thus beadministered once or twice a day.

Particularly preferred LABAs are formoterol, salmeterol and GSK-597901,milveterol, LAS 100977(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one),KUL-1248, carmoterol and indacaterol optionally in the form of theirracemates, their enantiomers, their diastereomers and mixtures thereof,and optionally their pharmacologically-compatible acid addition salts.More preferred are salmeterol, formoterol, LAS100977(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one),and indacaterol. Still more preferred are salmeterol, formoterol andLAS100977(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one),in particular salmeterol xinafoate, formoterol fumarate and LAS100977(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one).

For example, the invention provides a pharmaceutical composition forinhalation comprising aclidinium in the form of a dry powder of apharmaceutically acceptable salt, e.g., bromide, in admixture with apharmaceutically acceptable carrier, e.g., lactose particles, togetherwith formoterol fumarate, (i) comprising a single metered nominal doseof aclidinium equivalent to about 400 μg aclidinium bromide togetherwith a single metered nominal dose of about 5-25 μg (e.g. 6, 8.5, 12, 18or 24 μg, for example 12 μg) formoterol fumarate or (ii) in a multidosedry powder inhaler device calibrated to provide a metered nominal doseof aclidinium equivalent to about 400 μg aclidinium bromide togetherwith a metered nominal dose of about 5-25 μg (e.g. 6, 8.5, 12, 18 or 24μg, for example 12 μg) formotrol fumarate.

The pharmaceutical composition for inhalation comprising aclidinium anda β2-agonist, for example, formoterol or LAS100977(5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one),can be administered one or more times per day. Preferably once or twicea day.

Examples of suitable PDE4 inhibitors that can be combined withaclidinium in the present invention are benafentrine dimaleate,etazolate, denbufylline, rolipram, cipamfylline, zardaverine,arofylline, filaminast, tipelukast, tofimilast, piclamilast,tolafentrine, mesopram, drotaverine hydrochloride, lirimilast,roflumilast, cilomilast, oglemilast, apremilast,6-[2-(3,4-Diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid(tetomilast),(R)-(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine(CDP-840),N-(3,5-Dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide(GSK-842470), 9-(2-Fluorobenzyl)-N6-methyl-2-(trifluoromethyl)adenine(NCS-613), N-(3,5-Dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide(D-4418),N-[9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3(R)-yl]pyridine-4-carboxamide,3-[3-(Cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-isopropyl-3H-purinehydrochloride (V-11294A),6-[3-(N,N-Dimethylcarbamoyl)phenylsulfonyl]-4-(3-methoxyphenylamino)-8-methylquinoline-3-carboxamidehydrochloride (GSK-256066),4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridin-2(1H)-one(T-440),(−)-trans-2-[3′-[3-(N-Cyclopropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyridin-1-yl]-3-fluorobiphenyl-4-yl]cyclopropanecarboxylicacid (MK-0873), CDC-801, UK-500001, BLX-914,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluroromethoxyphenyl)cyclohexan]-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol,5(S)-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylbenzyl)piperidin-2-one(IPL-455903), ONO-6126 (Eur Respir J 2003, 22(Suppl. 45): Abst 2557) andthe compounds claimed in the PCT patent applications number WO03/097613,WO2004/058729, WO 2005/049581, WO 2005/123693 and WO 2005/123692.

Examples of suitable corticosteroids and glucocorticoids that can becombined with aclidinium in the present invention are prednisolone,methylprednisolone, dexamethasone, dexamethasone cipecilate, naflocort,deflazacort, halopredone acetate, budesonide, beclomethasonedipropionate, hydrocortisone, triamcinolone acetonide, fluocinoloneacetonide, fluocinonide, clocortolone pivalate, methylprednisoloneaceponate, dexamethasone palmitoate, tipredane, hydrocortisoneaceponate, prednicarbate, alclometasone dipropionate, Butixocortpropionate, RPR-106541, halometasone, methylprednisolone suleptanate,mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide,deprodone propionate, fluticasone propionate, fluticasone furoate,halobetasol propionate, loteprednol etabonate, betamethasone butyratepropionate, flunisolide, prednisone, dexamethasone sodium phosphate,triamcinolone, betamethasone 17-valerate, betamethasone, betamethasonedipropionate,21-Chloro-11beta-hydroxy-17alpha[2-(methylsulfanyl)acetoxy]-4-pregnene-3,20-dione,Desisobutyrylciclesonide, hydrocortisone acetate, hydrocortisone sodiumsuccinate, NS-126, prednisolone sodium phosphate, hydrocortisoneprobutate, prednisolone sodium metasulfobenzoate and clobetasolpropionate, especially budesonide or mometasone.

For example, the invention provides a pharmaceutical composition forinhalation comprising aclidinium in the form of a dry powder of apharmaceutically acceptable salt, e.g., bromide, in admixture with apharmaceutically acceptable carrier, e.g., lactose particles, togetherwith mometasone furoate, (i) comprising a single metered nominal dose ofaclidinium equivalent to about 400 μg aclidinium bromide together with asingle metered nominal dose of about 100-900 μg (e.g., 100, 110, 200,220, 300, 330, 400, 440, 800 or 880 μg, for example 200-450, e.g 220 or440 μg) mometasone furoate, or (ii) in a multidose dry powder inhalerdevice calibrated to provide a metered nominal dose of aclidiniumequivalent to about 400 μg aclidinium bromide together with a meterednominal dose of about 100-900 μg (e.g. 100, 110, 200, 220, 300, 330,400, 440, 800 or 880 μg, for example 200-450, e.g 220 or 440 μg)mometasone furoate.

The pharmaceutical composition for inhalation comprising aclidinium anda corticosteroid, for example mometasone furoate, can be administeredone or more times per a day. Preferably once or twice a day.

The invention also provides a pharmaceutical composition comprisingaclidinium, a β2-agonist as defined above and a corticosteroid, asdefined above. Most preferred β2-agonists are selected from LAS100977((5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(R)-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one)and formoterol. Most preferred corticosteroid is a mometasone furoate.These triple combinations are suitable for administration once or twicea day.

EXAMPLE 1

Methods: Patients with moderate to severe stable COPD were randomized toreceive double-blind, once-daily treatment with aclidinium (25, 50, 100,200, or 400 μg), placebo, or open-label tiotropium 18 μg for 4 weeks.Spirometric measurements were performed at 22-24 h after the first doseand then at weekly intervals, and from 0.5-6 h post-administration onDay 1 and at Week 4 (Day 29).

Results: The ITT population included 460 patients. Aclidiniumdose-dependently increased trough FEV₁ on Day 29 (table).

Mean change from baseline in trough FEV₁ on Day 29

Aclidinium Tiotropium (double-blind) (open-label) 25 μg 50 μg 100 μg 200μg 400 μg 18 μg n 65 65 69 66 67 64 Mean Δ, ml 39 36 83 148* 128* 161**p <0.05 vs placebo

Unlike tiotropium, the bronchodilatory effect of aclidinium during thefirst 6 h post-dose on Day 29 was comparable to that on Day 1 (alldoses). Time to peak FEV₁ was achieved at 3 h post-dose for aclidinium100-400 μg. Aclidinium was well tolerated, with no dose-dependent effecton ECG, laboratory parameters or adverse events.

Conclusion: Aclidinium produced sustained bronchodilation over 24 h andwas well tolerated. Aclidinium 200 and 400 μg had comparablebronchodilatory effects to open-label tiotropium 18 μg. Based on theefficacy and tolerability data, aclidinium 400 μg is selected as theinvestigational dose for a future long-term clinical trial in COPD.

The invention claimed is:
 1. A pharmaceutical composition comprisingaclidinium in the form of a dry powder of a pharmaceutically acceptablesalt in admixture with a pharmaceutically acceptable dry powder carrier,wherein the pharmaceutical composition is in a dosage form whichprovides a) a metered nominal dose of aclidinium equivalent to 400micrograms plus/minus 10% aclidinium bromide, b) an emitted dose ofaclidinium equivalent to 360 micrograms plus/minus 35% aclidiniumbromide, or c) a fine particle dose of aclidinium equivalent to 120micrograms plus/minus 35% aclidinium bromide, wherein the pharmaceuticalcomposition is for inhalation.
 2. The pharmaceutical compositionaccording to claim 1, in the form of a single-dose dry powderformulation comprising a) a single metered nominal dose of aclidiniumequivalent to about 400 micrograms plus/minus 10% aclidinium bromide, b)a single emitted dose of aclidinium equivalent to 360 microgramsplus/minus 35% aclidinium bromide, or c) a single fine particle dose ofaclidinium equivalent to 120 micrograms plus/minus 35% aclidiniumbromide.
 3. The pharmaceutical composition according to claim 1, in theform of a multi-dose dry powder formulation for administration in amultidose dry powder inhaler device calibrated to provide a meterednominal dose of aclidinium equivalent to about 400 micrograms plus/minus10% aclidinium bromide, b) an emitted dose of aclidinium equivalent to360 micrograms plus/minus 35% aclidinium bromide, or c) a fine particledose of aclidinium equivalent to 120 micrograms plus/minus 35%aclidinium bromide.
 4. The pharmaceutical composition according to claim1, wherein the pharmaceutically acceptable salt of aclidinium isaclidinium bromide.
 5. The pharmaceutical composition according to claim1, wherein the pharmaceutically acceptable carrier is lactose particles.6. The pharmaceutical composition according to claim 1, wherein theratio of aclidinium to carrier ranges from 1:25 to 1:75 by weight. 7.The pharmaceutical composition according to claim 6, wherein the ratioof aclidinium to carrier ranges from 1:50 to 1:75 by weight.
 8. Thepharmaceutical composition according to claim 1, wherein the averageparticle diameter of aclidinium ranges from 2 μm to 5 μm.
 9. Thepharmaceutical composition according to claim 1, wherein the carriercomprises particles having a d10 ranging from 90 μm to 160 μm, a d50ranging from 170 μm to 270 μm, and a d90 ranging from 290 μm to 400 μm.10. The pharmaceutical composition according to claim 1, furthercomprising an effective amount of at least one additional active agentchosen from β2-agonists, PDE IV inhibitors, and corticosteroids.
 11. Thepharmaceutical composition according to claim 10, wherein the at leastone additional active agent is chosen from formoterol, salmeterol,budesonide, and mometasone, wherein the at least one additional activeagent is in free or pharmaceutically acceptable salt form.
 12. Thepharmaceutical composition according to claim 11, wherein the at leastone additional active agent is formoterol fumarate in an amount rangingfrom about 5 micrograms to 25 micrograms per metered nominal dose. 13.The pharmaceutical composition according to claim 12, wherein formoterolfumarate is present in an amount of about 6 micrograms per meterednominal dose.
 14. The pharmaceutical composition according to claim 12,wherein formoterol fumarate is present in an amount of about 12micrograms per metered nominal dose.
 15. A method of treating arespiratory condition chosen from asthma and chronic obstructivepulmonary disease, comprising administering a pharmaceutical compositioncomprising aclidinium in the form of a dry powder of a pharmaceuticallyacceptable salt in admixture with a pharmaceutically acceptable drypowder carrier; wherein the pharmaceutical composition is in a dosagefrom which provides: a) a metered nominal dose of aclidinium equivalentto 400 micrograms plus/minus 10% of aclidinium bromide, b) an emitteddose of aclidinium equivalent to 360 micrograms plus/minus 35%aclidinium bromide, or c) a fine particle dose of aclidinium equivalentto 120 micrograms plus/minus 35% aclidinium bromide, by inhalation to apatient in need of such treatment.
 16. The method of claim 15, furthercomprising administering an effective amount of at least one additionalactive agent chosen from β2-agonists, PDE IV inhibitors, andcorticosteroids.
 17. The method of claim 16, wherein the at least oneadditional active agent is chosen from formoterol, salmeterol,budesonide, and mometasone, wherein the at least one additional activeagent is in free or pharmaceutically acceptable salt form.
 18. Themethod according to claim 17, wherein the at least one additional activeagent is formoterol fumarate in an amount ranging from about 5micrograms to 25 micrograms per metered nominal dose.
 19. The methodaccording to claim 17, wherein the at least one additional active agentis mometasone furoate in an amount ranging from about 100 micrograms to900 micrograms per metered nominal dose.
 20. The method of claim 15,wherein the dose is a twice-daily dose of a) a metered nominal dose ofaclidinium equivalent to 400 micrograms plus/minus 10% of aclidiniumbromide, b) an emitted dose of aclidinium equivalent to 360 microgramsplus/minus 35% aclidinium bromide, or c) a fine particle dose ofaclidinium equivalent to 120 micrograms plus/minus 35% aclidiniumbromide.
 21. The method of claim 15, wherein the dose is a single-dailydose of a) a metered nominal dose of aclidinium equivalent to 400micrograms plus/minus 10% of aclidinium bromide, b) emitted dose, ofaclidinium equivalent to 360 micrograms plus/minus 35% aclidiniumbromide, or c) a fine particle dose of aclidinium equivalent to 120micrograms plus/minus 35% aclidinium bromide.
 22. A multidose dry powderinhaler device comprising a pharmaceutical composition comprisingaclidinium in the form of a dry powder of a pharmaceutically acceptablesalt in admixture with a pharmaceutically acceptable dry powder carrier,wherein the pharmaceutical composition is in a dosage form whichprovides, and the device is calibrated to deliver upon actuation: a) ametered nominal dose of aclidinium equivalent to 400 microgramsplus/minus 10% of aclidinium bromide, b) an emitted dose of aclidiniumequivalent to 360 micrograms plus/minus 35% aclidinium bromide, or c) afine particle dose of aclidinium equivalent to 120 micrograms plus/minus35% aclidinium bromide.